Methods of treating optic disorders

ABSTRACT

The present invention relates to methods for treating optic disorders or for reducing or alleviating the signs, symptoms, or pathological conditions related to such optic disorders. In particular, methods are provided for treating optic disorders, or reducing the symptoms thereof, the methods involving the administration of one or more downstream folate compounds and/or methyl-B12. In one particular embodiment, the method comprises administration of L-methylfolate. In other embodiments, the method involves administering both L-methylfolate and methyl-B12. In still further embodiments, the method further involves reducing dietary intake of folic acid. In certain embodiments, the method further involves identifying a subject organism with a malfunction in one or more of the folate or B4 cycles. In certain embodiments, such a malfunction is one or more of the C677T and A1298C mutations. In still further embodiments, the method further involves identifying a subject organism that is deficient in vitamins B-12 and D3 but which possesses excess homocysteine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S patent application Ser. No.15/714,802 filed Sep. 25, 2017, which is a divisional of U.S. patentapplication Ser. No. 14/459,771 filed Aug. 14, 2014, which is acontinuation of U.S. application Ser. No. 13/166,207 filed Jun. 22, 2011which claims the benefit of United States Provisional Application No.61,358,522 filed on Jun. 25, 2010. The disclosure of each of thesedocuments is hereby incorporated in its entirety by reference.

FIELD OF THE INVENTION

The invention relates to methods of treating optic disorders usingdownstream folate compounds and/or methylcobalamin.

BACKGROUND OF THE INVENTION

Disorders causing visual impairment are numerous. Optic neuropathy is amedical disorder involving visual impairment related to optic nervedamage. The primary symptom of optic neuropathy is vision loss, which isgenerally bilateral, painless, gradual, and progressive. This visionloss often initially presents as a change in color vision, ordyschromatopsia, and also often begins with a centralized blurring,followed by a progressive decline in visual acuity. The vision loss fromoptic neuropathy can result in total blindness. Other clinical diagnosesfrequently accompany optic neuropathy, including optic nerve headdrusen, or accumulations of extracellular material on the optic nervehead, and/or papillitis, or inflammation of the optic nerve head.

There are many forms of optic neuropathy which are generally delineatedbased upon the cause of the neuropathy. One such form is toxic opticneuropathy, meaning nerve damage resulting from the presence of toxiccompounds, such as methanol, ethylene glycol, ethambutol, or certainantibiotics. Another form of optic neuropathy is nutritional opticneuropathy, which is caused by certain nutritional deficiencies. Themost common nutritional deficiencies that result in optic neuropathy areB-vitamin deficiencies, such as thiamine, niacin, riboflavin, or folicacid deficiency. (See, e.g., Glaser J S: Nutritional and toxic opticneuropathies. In: Glaser J S, ed., Neuro-ophthalmology. 3rd ed.Philadelphia: Lippincott Williams & Wilkins; 1999: 181-6; Lessell S:Nutritional deficiency and toxic optic neuropathies. In: Albert D M,Jakobiec F A, eds., Principles and Practice of Ophthalmology. 2nd ed.Philadelphia: W.B. Saunders Company; 2000: 4169-76; and Phillips P:Toxic and deficiency optic neuropathies. In: Miller N R, Newman N J,Walsh F B, Hoyt W F, eds., Walsh and Hoyt's ClinicalNeuro-ophthalmology. 6th ed. Philadelphia: Lippincott Williams &Wilkins; 2005: 447-63). In cases of nutritional optic neuropathy, thetreatment generally employed is to increase the intake of the deficientnutrient. For example, when the optic neuropathy is caused by folic aciddeficiency, the disorder can be successfully treated by folic acidsupplementation (see, e.g., P. de Silva, et al., Folic acid deficiencyoptic neuropathy: A case report, Journal of Medical Case Reports 2:299(2008)).

Retinopathies are another common optic disorder. Retinopathies aredisorders that present as non-inflammatory damage to the retina of theeye. Like neuropathies, retinopathies can have numerous causes and arefrequently delineated based upon their cause, such as diabeticretinopathy, hypertensive retinopathy, and genetic retinopathy. (Wright,et al., Homocysteine, folates, and the eye, Eye (Land), August, 2008,22(8):989-93, available online Dec. 7, 2007; Abu El-Asrar, et al.,Hyperhomocysteinemia and retinal vascular occlusive disease, Eur. J.Ophthalmol., November-December 2002, 12(6):495-500; Becker et al.,Epidemiology of homocysteine as a risk factor in diabetes, Metab. Syndr.Relat. Disord., June 2003, 1(2)105-20; Faye A Fishman, The Gale GroupInc., Gale, Detroit, Gale Encyclopedia of Medicine, 2002).

Macular degeneration is yet another common optic disorder. Maculardegeneration is an optic disorder characterized by vision loss due todamage to the center of the retina, or macula. This retinal damage iscaused by damage to the blood vessels that supply that macula. To alarge extent, it is unknown what ultimately causes this blood vesseldamage that results in macular degeneration and there is no knowntreatment for macular degeneration at this time, though vitaminsupplements have been suggested to slow the progression of maculardegeneration. (Health News, B vitamins may be “silver bullet” forage-related macular degeneration: Daily supplementation with folic acidplus vitamins B6 and B12 may reduce risk of AMD by 35-40 percent, May2009, 15(5):8-9; Mary Bekker, The Gale Group Inc., Gale, Detroit, GaleEncyclopedia of Nursing and Allied Health, 2002).

Dry Eye Syndrome is still another optic disorder. This disorder, alsocalled Keratoconjunctivitis Sicca (KCS) or Keratitis Sicca, is caused bydecreased tear production or increased tear film evaporation. Thisdisorder is usually bilateral and is characterized by dryness andirritation of the eye, frequently getting worse as the day goes on.(“Keratoconjunctivitis Sicca” in The Merck Manual, Home Edition, Merck &Co., Inc., 2003, available athttp://www.merck.com/mmhe/sec20/ch230/ch230d.html.).

Folate is a required nutrient and is frequently added to processedfoods, such as cereals and breads, in the form of folic acid. However,folic acid is not itself a generally useful form of folate from ametabolic standpoint. Instead, folic acid is converted, through a seriesof enzymatic steps, to more metabolically active forms of folate via thefolate cycle. In the folate cycle, folic acid is first converted intodihydrofolate (DHF) in the presence of vitamin B3. Also with the aid ofvitamin B3, DHF is in turn converted into tetrahydrofolate (THF). THF isthen converted into 5,10-methylenetetrahydrofolate (5,10-METHF), eitherdirectly or via 5-formiminotetrahydrofolate (5FITHF) and5,10-methenyltetrahydrofolate intermediates. As a part of this samegeneral process, 5-formyltetrahydrofolate (folinic acid), another folatecompound, is also converted into 5,10-METHF, again via a5,10-methenyltetrahydrofolate intermediate. Finally, 5,10-METHF isconverted to 5-methyltetrahydrofolate (5MTHF), also calledL-methylfolate, levomefolic acid, levomefolate,(6S)-5-methyltetrahydrofolate (6S-5MTHF), which is the predominantmetabolically active form of folate. (Hasselwander et al.,5-Methyltetrahydofolate—the active form of folic acid, Functional Foods,2000 Conference Proceedings, pp 48-59; Kelly et al., Unmetabolized folicacid in serum: acute studies in subjects consuming fortified food andsupplements, Am. J. Clin. Nutr., 1997, 65:1790-95).

While this is the ideal path for metabolism of folic acid, as many as50% of population may have a reduced ability to effectively convertfolic acid into its useable form. (Klerk et al., MTHFR 677 C-Tpolymorphism and risk of coronary heart disease: A Meta-analysis, JAMA,2002, 288:2023-30). Because of this, it is possible to have insufficientamounts of metabolically useful folate despite having adequate folicacid intake.

The folate cycle is not isolated, but rather interacts with, and in somecases is intertwined with, other metabolic cycles. For example, thefolate cycle interacts with the methylation cycle (also known as themethionine cycle), which produces methionine from homocysteine. Morespecifically, 5MTHF produced by the folate cycle donates a methyl groupwhich ultimately allows methionine to be produced from homocysteine.Additionally, the folate cycle interacts with the BH4 cycle, whichproduces tetrahydrobiopterin (BH4) from dihydrobiopterin (BH2). In thiscase, the interaction between the cycles involves both cycles utilizinga common enzyme: methylenetetrahydrofolatereductase (MTHFr). Because ofthese complex interactions, malfunctions in one cycle can causesubsequent malfunctions in the other, related cycles. For example, if anindividual has a malfunction in the folate cycle such that insufficient5MTHF is produced, this can cause a buildup of homocysteine and adeficiency of methionine due to an inability of that individual to usethe former to produce the latter.

Vitamin B-12 is also intimately linked to the folate cycle. Forinstance, vitamin B-12 is an important cofactor in the metabolism ofintermediate folate compounds, as well as being involved in multiplepathways that utilize L-methylfolate. One example of vitamin B-12'sinvolvement in a pathway that involves L-methylfolate is again in theconversion of homocysteine into methionine. As stated above, 5MTHFdonates a methyl group that eventually results in conversion ofhomocysteine into methionine. That methyl group is transferred from5MTHF to cobalamin, an unmethylated form of vitamin B-12, therebyproducing the methyl form of vitamin B-12, methylcobalamin (also calledmethyl-B12). Methylcobalamin in turn donates the methyl group tohomocysteine to convert it into methionine. Thus, if an individual hasan inadequate supply of vitamin B-12, the conversion of homocysteine tomethionine will be negatively impacted. Vitamin B-12 is also importantin other ways, such as being necessary for nerve repair and nervehealth. Because of this, deficiencies in vitamin B-12 andmethylcobalamin in particular, can lead to serious complications, suchas pernicious anemia.

Because the cycles in which many of these nutrients are involved containmultiple enzymatic steps, they are prone to malfunction. Suchmalfunction can result, for example, from environmental toxins, ingestedchemical compounds or toxins, metabolic imbalances, or geneticpolymorphisms in the enzymes which carry out the process steps. Forinstance, the enzyme MTHFr is involved in the folate cycle. Morespecifically, this enzyme is at least partially responsible forconverting 5,10-METHF into 5MTHF. Mutations in the portion of thisenzyme that is involved in this conversion are known to exist. One suchmutation, the C677T mutation, is known to slow down the folate cycleactivity of this enzyme, resulting in reduced production of 5MTHF fromits precursor product(s). For instance, individuals with this particularpolymorphism have reduced CNS L-methylfolate. (Surtees et al.,Association of cerebrospinal fluid deficiency of5-methyltetrahydrofolate, but not S-adenosylmethionine, with reducedconcentrations of the acid metabolites of 5-hydroxytryptamine anddopamine, Clinical Science, 1994, 86:697-702). Moreover, approximately70% of patients with diabetic retinopathy have this geneticpolymorphism. (Sun et al., The relationship between MTHFR genepolymorphisms, plasma homocysteine levels and diabetic retinopathy intype 2 diabetic meilitus, Chin. Med. J., 2003, 116 (1): 145-7).

MTHFr is also susceptible to mutation in those portions of the enzymewith activities outside the folate cycle. For instance, another functionof MTHFr is the conversion of dihydrobiopterin (BH2) totetrahydrobiopterin (BH4) in the BH4 cycle. BH4 is subsequently involvedin multiple other biological pathways and is essential in the synthesisof numerous catecholamines (e.g., dopamine andnoradrenaline/norepinephrine) and indolamines (e.g., serotonin andmelatonin), as well nitric oxide synthases, which are involved in immunefunctions as well as vascularization. As such, a mutation in the portionof MTHFr responsible for BH4 cycle activity, such as the A1298Cpolymorphism, can cause a disruption in the BH4 pathway and subsequentmalfunctions in numerous downstream pathways. For example, the A1298Cpolymorphism has been associated with glaucoma, with higher incidence ofcardiovascular disease, and with incidence of eye disease, such asretinopathy. (Shazia et al., MTHFR and A1298C polymorphism andhomocysteine levels in primary open angle and primary closed angleglaucoma, Molecular Vision, 2009, 15:2268-2278; Haviv et al., The commonmutations C677T and A1298C in the human methylenetetrahydrofolatereductase gene are associated with hyperhomocysteinemia andcardiovascular disease in hemodialysis patients, Nephron, September2002, 92(1):120-6; Targher et al., Diabetic retinopathy is associatedwith an increased incidence of cardiovascular events in Type 2 diabeticpatients., Diabetic Medicine, 2008, 25:45-50).

Moreover, because these multiple cycles are intricately intertwined, asingle malfunction can have far-reaching effects. Anything that breaksdown the methylation cycles impacts nitric oxide levels, affects redblood cell function, increases inflammation, causes immune systemmalfunctions, causes detoxification system malfunctions, causesantioxidant system malfunctions, and negatively impacts our ability toheal and repair. The results of this are reduced blood flow and reducedred blood cells, both of which cause less nutrients and oxygen to get tothe eyes; increased inflammation; and reduced detoxification. All ofthis has been linked to Diabetic retinopathy, Glaucoma, Dry Eyes,Age-related macular degeneration (AMD), branch retinal artery occlusion,a central retinal artery occlusion, a branch retinal vein occlusion, acentral vein occlusion, optic neuropathy, and optic neuritis.

Because of the fortification of many processed foods, such as cerealsand breads, with folic acid, excessive levels of folic acid may exist inmuch of the human population. For instance, the U.S. National Academy ofSciences recommends a daily intake of 150-600 .mu.g of folic aciddepending on the individual's age and pregnancy status. Many folic acidfortified breakfast cereals supply this amount in a single serving, asdo many daily multivitamins. In addition, fortified breads frequentlysupply 5-10% (or more) of the daily requirement in a single slice, whileother fortified grains, such as rice, frequently supply 10-20% (or more)of the daily requirement in a single serving. Because of this, it isvery common for an individual to have well over twice, and sometimesupwards of four times, the recommended daily intake of folic acid. (USDANational Nutrient Database for Standard Reference, Release 22, Contentof Selected Foods per Common Measure, Folate, DFE sorted by nutrientcontent).

This is somewhat troubling given that it has been suggested thatexcessive levels of folic acid might be detrimental in several regards.For instance, some studies have suggested an antagonistic effect ofexcess folic acid on the metabolically active form by demonstrating aninverse relationship between the amount of unmetabolized folic acid inthe blood and the ability of L-methylfolate to cross cell membranes.(Wollack et al., Characterization of folate uptake by choroid plexusepithelial cells in a rat primary culture model, J. Neurochem. 2008;104:1494-1503; Reynolds, Benefits and risks of folic acid to the nervoussystem, J. Neurol. Neurosurg. Psychiatry, 2002, 72:567-71).

Further, unmetabolized folic acid has been linked to increased risk ofcancer, growth of abnormal cells, increased depression, neurologicalcomplications, and decreased immune response. (Troem et al.,Unmetabolized Folic Acid in Plasma Is Associated with Reduced NaturalKiller Cell Cytotoxicity among Postmenopausal Women, J. Nutr., 2006,136:189-194; Smith et al., Pteridines and mono-amines: relevance toneurological damage, Postgrad. Med. J., 1986, 62(724):113-23; Asien etal., High-dose B vitamin supplementation and cognitive decline inAlzheimer disease: a randomized controlled trial, JAMA, 2008,300(15):1774-83). The presence of unmetabolized folic acid in the bodyhas not heretofore been linked with pathological conditions of the eye.However, active folate and active vitamin B-12 have been found toimprove corneal nerve fiber density (CNFD) and branch density, forexample in patients with diabetic neuropathies. (Quattrini et al.,Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy,Diabetes, 2007, 56(8):2148-54).

SUMMARY OF THE INVENTION

The present invention is directed toward methods of treating opticdisorders using downstream folate compounds and, optionally,methylcobalamin. One aspect of the present invention is a method ofimproving or alleviating an optic disorder or the symptoms relatedthereto in a non-folic acid-deficient subject organism, the methodcomprising a) identifying a non-folic acid-deficient subject organismsuffering from an optic neuropathy, and b) administering to the subjectorganism an effective amount of one or more downstream folate compounds.In other aspects, the invention further involves c) decreasing thesubject organism's intake of folic acid.

In certain embodiments of the present invention, the subject organism isa human. In other embodiments, the one or more downstream folatecompounds are selected from the group consisting of DHF, THF, 5FITHF,5,10-METHF, and L-methylfolate. In particular embodiments, thedownstream folate compounds comprise L-methylfolate. In other particularembodiments, the L-methylfolate is provided in a dose of 1 mcg-25mg/day. In other embodiments, the L-methylfolate is provided in a doseof 1-25 mg/day.

Another aspect of the present invention is a method of improving visualacuity in a subject organism, the method comprising 1) identifying anon-folic acid-deficient subject organism with a) reduced visual acuity,b) an optic disorder which can cause reduced visual acuity, and c) amalfunction in one or more of the folate cycle and BH4 cycle; and 2)administering to the subject organism an effective amount of one or moredownstream folate compounds to improve the subject organism's visualacuity. In other aspects, the invention further involves 3) decreasingthe subject organism's intake of folic acid.

In certain embodiments of the present invention, the malfunction in oneor more of the folate cycle and BH4 cycle is one or more of the C677Tand A1298C mutations. In certain other embodiments, the subject organismpossesses both of the C677T and A1298C mutations. In still furtherembodiments, the optic disorder is selected from the group consisting ofoptic neuropathy, retinopathy, macular degeneration, or optic atrophy.In yet other embodiments, the subject organism is a human. In stillfurther embodiments, the one or more downstream folate compounds areselected from the group consisting of DHF, THF, 5FITHF, 5,10-METHF, andL-methylfolate. In certain embodiments, the downstream folate compoundscomprise L-methylfolate. In particular embodiments, the L-methylfolateis provided in a dose of 1-25 mg/day.

Yet another aspect of the present invention is a method of improvingvisual acuity in a subject organism, the method comprising 1)identifying a subject organism with a) reduced visual acuity, b) anoptic disorder which can cause reduced visual acuity, c) a malfunctionin one or more of the folate cycle and BH4 cycle, d) above normalhomocysteine levels, and e) deficiencies in vitamin B-12 and vitamin D;and 2) administering to the subject organism an effective amount of oneor more downstream folate compounds and methyl-B12. In other aspects,the invention further involves 3) decreasing the subject organism'sintake of folic acid In yet other aspects, the invention furtherinvolves administering an effective amount of one or both of vitamin B6and vitamin D3.

In certain embodiments of the present invention, the malfunction in oneor more of the folate cycle and BH4 cycle is one or more of the C677Tand A1298C mutations. In certain other embodiments, the subject organismpossesses both of the C677T and A1298C mutations. In still furtherembodiments, the optic disorder is selected from the group consisting ofoptic neuropathy, retinopathy, macular degeneration, or optic atrophy.In yet other embodiments, the subject organism is a human. In stillfurther embodiments, the one or more downstream folate compounds areselected from the group consisting of DHF, THF, 5FITHF, 5,10-METHF, andL-methylfolate. In certain embodiments, the downstream folate compoundscomprise L-methylfolate. In particular embodiments, the L-methylfolateis provided in a dose of 1-25 mg/day.

In other particular embodiments, the methyl-B12 is administered in adose of 1-2.5 mg/day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the major steps and intermediates involved in the folatecycle and the interaction of the folate cycle with the methionine cycle.

DESCRIPTION OF THE INVENTION

The present invention springs, in part, from the inventor's surprisingdemonstration of the successful treatment of several optic disordersusing folate, optionally in combination with one or more of methyl-B12,vitamin B6, and vitamin D3, in patients who possessed some type ofmetabolic abnormality associated with folic acid metabolism orintertwined metabolic cycles. The inventor has successfully treatedindividuals with neuropathies, retinopathies, macular degeneration, andassociated ocular pathologies by administering one or more downstreamfolate compounds and, optionally, one or more of methyl-B12, vitamin B6,vitamin D3, and reduced folic acid intake.

The present invention thus relates to methods of treating opticdisorders or reducing or alleviating the signs, symptoms, orpathological conditions related to such optic disorders. In certainembodiments, the invention relates to methods of treating opticdisorders using downstream folate compounds to negate the occurrence ofenvironmental, medication, lifestyle, disease, or genetically inducedinterference and/or disruption in specific biochemical reactionsnecessary for normal vision. In certain embodiments, methods areprovided for treating optic disorders, or reducing the symptoms thereof,the methods involving the administration of one or more downstreamfolate compounds. In one particular embodiment, the method comprisesadministration of L-methylfolate. In other embodiments, the methodfurther involves reducing dietary intake of folic acid. In certain otherembodiments, the method further involves administering methyl-B12. Instill further embodiments, the method further comprises administeringone or more of vitamin B6 and vitamin D3. In still other embodiments,the method further involves first identifying a subject organism with anoptic disorder which individual is not folic acid deficient. In stillfurther embodiments, the method involves identifying a subject organismwith a malfunction in one or more of the folate or B4 cycles. In certainembodiments, such a malfunction is one or more of the C677T and A1298Cmutations. In still further embodiments, the method further involvesidentifying a subject who is vitamin B12 and D3 deficient and who haselevated levels of homocysteine. In other embodiments, the methodinvolves identifying a subject organism which is not folic aciddeficient.

The entire contents of all references cited in this disclosure arespecifically incorporated by reference herein. Further, when an amount,concentration, or other value or parameter is given as either a range,preferred range, or a list of upper preferable values and lowerpreferable values, this is to be understood as specifically disclosingall ranges formed from any pair of any upper range limit or preferredvalue and any lower range limit or preferred value, regardless ofwhether ranges are separately disclosed. Where a range of numericalvalues is recited herein, unless otherwise stated, the range is intendedto include the endpoints thereof, and all integers and fractions withinthe range. It is not intended that the scope of the invention be limitedto the specific values recited when defining a range.

In this disclosure, a number of terms and abbreviations are used. Thefollowing definitions are provided.

As used herein, “comprising” is to be interpreted as specifying thepresence of the stated features, integers, steps, reagents, orcomponents as referred to, but does not preclude the presence oraddition of one or more features, integers, steps or components, orgroups thereof. Thus, for example, a composition comprising onedownstream folate compound may comprise more downstream folate compoundsthan those actually recited, i.e., it may comprise two or more distinctdownstream folate compounds. Additionally, the term “comprising” isintended to include embodiments encompassed by the terms “consistingessentially of” and “consisting of”. Similarly, the term “consistingessentially of” is intended to include embodiments encompassed by theterm “consisting of”.

In certain embodiments, the term “about,” when used in conjunction witha numerical variable, limitation, or range means plus or minus 5%. Inother embodiments, the term “about,” when used in conjunction with anumerical variable, limitation, or range means plus or minus 1%.

The term “downstream folate compound” or “downstream folate” means afolate compound downstream of folic acid in the folate cycle. The“folate cycle” refers to the process by which metabolicallyunrecognizable/inactive folates are converted into metabolicallyuseful/recognizable/active folates in the body. FIG. 1 shows the majorsteps and intermediates involved in the folate cycle. As can be seen,during the folate cycle, folic acid is first converted intodihydrofolate (DHF), which is in turn converted to tetrahydrofolate(THF). THF is then converted into 5,10-methylenetetrahydrofolate(5,10-METHF), either directly or via 5-form iminotetrahydrofolate(5FITHF) and 5,10-methenyltetrahydrofolate intermediates. As a part ofthis same general process, 5-formyltetrahydrofolate (folinic acid),another folate compound, is also converted into 5,10-METHF, again via a5,10-methenyltetrahydrofolate intermediate. 5,10-METHF is then convertedto 5-methyltetrahydrofolate (5MTHF), also called L-methylfolate,levomefolic acid, levomefolate, (6S)-5-methyltetrahydrofolate(6S-5MTHF), which is the predominant metabolically active form offolate. L-methylfolate is also referred to at various times and/or byvarious pharmaceutical manufacturers as L-5-Methyltetrahydrofolate,L-5-MTHF, and L-MTHF. The enzyme methylenetetrahydrofolatereductase(MTHFr) is at least partially responsible for converting 5,10-METHF into5MTHF. Thus, folate compounds downstream of folic acid in the folatecycle include DHF, THF, 5FITHF, 5,10-methenyltetrahydrofolate,5,10-METHF, and L-methylfolate. Downstream folate compounds areincluded, for example, in certain commercially available dietarysupplements, including, but not limited to, Metafolin® available fromMerck; CerefolinNAC®, Deplin®, and Metanx® available from Pamlab; andQuatrefolic® available from Gnosis.

As used herein, the term “BH4 cycle” means the cycle responsible for theconversion of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4). Oneenzyme involved in this cycle is MTHFr.

As used herein, “methyl-B12” refers to methylcobalamin.

As used herein, a “malfunction” in the folate or BH4 cycle means anexogenous or endogenous condition which negatively affects the normaloperation of the folate cycle and/or BH4 cycle. Such malfunctions couldresult, for example, from environmental toxins, ingested chemicalcompounds or toxins, metabolic imbalances, or genetic disorders ormutations affecting enzymes in the folate and/or BH4 cycle, includingthe C677T and/or A1298C genetic mutations.

As used herein, “C677T” refers to a mutation in one or more alleles of agene encoding the MTHFr enzyme where the cytosine nucleotide atnucleotide position 677 of the MTHFr gene is replaced with a thyminenucleotide. This mutation results in a malfunction in the enzyme'sfolate cycle activity.

As used herein, “A1298C” refers to a mutation in one or more alleles ofa gene encoding the MTHFr enzyme where the adenine nucleotide atnucleotide position 1298 of the MTHFr gene is replaced with a cytosinenucleotide. This mutation results in a malfunction in the enzyme's BH4cycle activity.

As used herein, “optic disorder” means a disorder or malfunction whichresults in physical disease or a pathological condition of the eye orrelated structures, such as drusen, papillitis, optic neuropathy,retinopathy, or vitreous hemorrhage; and/or other vision-related signsor symptoms, such as reduced visual acuity, optic field defect, orvision related headaches. Optic disorders include toxic opticneuropathy, nutritional optic neuropathy, viral optic neuropathy,hypertension retinopathy, diabetic retinopathy, macular degeneration,optic atrophy, and optic nerve inflammation. “Toxic optic neuropathy” asused herein can include optic neuropathy resulting from toxic amounts ofunmetabolized folic acid that have accumulated in an individual, such asan individual who is impaired in metabolizing folic acid to downstreamfolate compounds. In addition, “toxic optic neuropathy” can includeoptic neuropathy resulting from toxic amounts of cyanocobalamin, a formof vitamin B-12 commonly found in dietary supplements, that haveaccumulated in an individual, such as an individual who is impaired inthe ability to metabolize cyanocobalamin or to convert it into otherforms of vitamin B-12, such as methyl-B12.

“Visual acuity” refers to the clarity and/or sharpness of the subjectorganism's vision. “Reduced visual acuity” means a visual acuity belowwhat is generally accepted as normal or typical for that particularsubject organism. For example, in an adult human, reduced visual acuitywould include visual acuity less than 20/20, e.g., 20/40 vision.

The term “non-folic acid-deficient” means a subject organism that hasbeen found to not have a deficiency in folic acid, i.e., in folic acidas provided in the diet or through dietary supplementation, and asmeasured in the blood serum following such intake. A determination thata subject organism does not have a folic acid deficiency can be made byany number of suitable tests or analyses to determine folic acid orfolate levels in the body. Such tests are well known to persons ofordinary skill in the art and include analysis of folic acid levels inthe blood plasma and/or analysis of folic acid levels within red bloodcells. In addition, a determination that a subject organism does nothave a folic acid deficiency can be made through an analysis of asubject organism's dietary intake of folic acid. If such an analysisreveals that an adequate amount of folic acid is being consumed throughthe diet, then the subject organism is non-folic acid-deficient. Forexample, a non-folic acid-deficient subject includes a person whoconsumes at least the appropriate recommended daily allowance of folicacid as established by the U.S. National Academy of Sciences. Incontrast, a folic acid deficient individual would include a person knownto consume far below the recommended daily allowance of folic acid.

As used herein, a nutritional “deficiency,” such as a deficiency invitamin B-12, methyl-B12, vitamin D3, or vitamin B6, means the subjectorganism possesses a level of the nutrient of interest that is less thanthe level that is generally accepted as normal by persons of ordinaryskill in the art. Such levels are well known to persons of ordinaryskill in the art, as are methods for determining a particular subjectorganism's levels of nutrients of interest. Methods of testing includeblood tests for nutrients of interest.

As used herein, “subject organism” means any animal, regardless ofspecies, gender, or age, capable of meeting the other criteria of theinvention (e.g., non-folic acid-deficient with an optic neuropathy). Incertain embodiments, the subject organism is a mammal. In certain otherembodiments, the subject organism is a companion animal, preferably adog, cat, horse, or bird. In other embodiments, the subject organism isa human.

As used herein, an “effective amount” is an amount of a compound, suchas a downstream folate compound, methyl-B12, vitamin B6, or vitamin D3,that is sufficient to cause favorable changes in the subject organism'soptic disorder. For instance, an effective amount of downstream folateincludes a sufficient amount of a downstream folate compound to causeimproved visual acuity when provided regularly over a period of days toyears. An effective amount similarly includes a sufficient amount of adownstream folate compound to cause reduced drusen and/or papillitiswhen provided regularly over a period of days to years.

In certain embodiments, an effective amount of a downstream folatecompound is about 1 mcg-25 mg per day, about 1-20 mg per day, about2.8-15 mg per day, or about 5-10 mg per day. In other embodiments, aneffective amount of a downstream folate compound is about 1 mcg per day,about 10 mcg per day, about 20 mcg per day, about 30 mcg per day, about40 mcg per day, about 50 mcg per day, about 60 mcg per day, about 70 mcgper day, about 80 mcg per day, about 90 mcg per day, about 100 mcg perday, about 200 mcg per day, about 300 mcg per day, about 400 mcg perday, about 500 mcg per day, about 600 mcg per day, about 700 mcg perday, about 800 mcg per day, about 900 mg per day, about 1 mg per dayabout 1.5 mg per day, about 2 mg per day, about 2.5 mg per day, about2.8 mg per day, about 3 mg per day, about 3.5 mg per day, about 4 mg perday, about 4.5 mg per day, about 5 mg per day, about 6 mg per day, about7 mg per day, about 7.5 mg per day, about 8 mg per day, about 9 mg perday, about 10 mg per day, about 11 mg per day, about 12 mg per day,about 13 mg per day, about 14 mg per day, about 15 mg per day, about 16mg per day, about 17 mg per day, about 18 mg per day, about 19 mg perday, about 20 mg per day, about 21 mg per day, about 22 mg per day,about 23 mg per day, about 24 mg per day, or about 25 mg per day. Incertain other embodiments, an effective amount of a downstream folatecompound is about 10 mcg-200 mg per week, about 100 mcg-200 mg per week,about 1-200 mg per week, about 5-150 mg per week, about 10-125 mg perweek, about 19.6-105 mg per week, about 20-100 mg per week, about 25-90mg per week, about 30-80 mg per week, about 35-70 mg per week, about40-60 mg per week, or about 50-55 mg per week. In other embodiments, aneffective amount of a downstream folate compound is about 5-1000 mg permonth, about 20-900 mg per month, about 40-800 mg per month, about50-700 mg per month, about 60-600 mg per month, about 80-500 mg permonth, about 100-400 mg per month, about 150-300 mg per month, or about200-250 mg per month.

In certain embodiments, an effective amount of methyl-B12 is about 1 mcgto about 10 mg per day, about 0.5-5 mg per day, or about 1-2.5 mg perday. In other embodiments, an effective amount of methyl-B12 is about0.5-100 mg per week, about 3-35 mg per week, or about 7-17.5 mg perweek. In other embodiments, an effective amount of methyl-B12 is about2-300 mg per month, about 15-150 mg per month, or about 30-75 mg permonth.

In other embodiments, multiple compounds are administered, such asfolate and methyl-B12, or folate, methyl-B12 and one or more of vitaminB6 and D3. In such cases, an effective amount of each component is anamount sufficient to cause favorable changes in the subject organism'soptic disorder when the components are administered in the desiredcombination.

It should also be noted that these amounts do not need to be supplied ina single dose, but rather can be supplied in multiple daily, weekly, ormonthly doses. For example, dosages can be 1 time per day, 2 times perday, 3 times per day, 4 times per day, 5 times per day, 6 times per day,7 times per day, 1 time per week, 2 times per week, 3 times per week, 4times per week, 5 times per week, 6 times per week, 7 times per week, 1time per month, 2 times per month, 3 times per month, 4 times per month,5 times per month, 6 times per month, 7 times per month, 8 times permonth, 9 times per month, 10 times per month, 11 times per month, 12times per month, 13 times per month, 14 times per month, 15 times permonth, 16 times per month, 17 times per month, 18 times per month, 19times per month, 20 times per month, 21 times per month, 22 times permonth, 23 times per month, 24 times per month, 25 times per month, 26times per month, 27 times per month, 28 times per month, 29 times permonth, 30 times per month, or 31 times per month.

In addition, the administration of the effective amount of one or moredownstream folate compounds can continue for a period of days to years.For instance, in certain embodiments, the downstream folate compound(s)are administered on a regular basis for at least 1 day, 2 days, 3 days,4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months,15 months, 16 months, 17 months 18 months, 2 years, 3 years, 4 years, 5years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years,13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20years, or the remaining duration of the subject organism's life. Inother embodiments, the downstream folate compound(s) are administered ona regular basis for less than 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 2 months, 3 months,4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months,11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17months 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years,8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15years, 16 years, 17 years, 18 years, 19 years, 20 years, or theremaining duration of the subject organism's life.

The compounds being administered can be supplied in any form and by anyroute known in the art, for example, orally (e.g., tablet, capsule,liquid, oral suspension, etc.), transdermally (e.g., ointment, patch,etc.), sublingually, subcutaneously, intramuscularly, rectally, in dropform, or intravenously. In certain other embodiments, oral doses can beprovided in a time release or extended release form.

Methyl-B12 is available from numerous sources, such as Source Naturals,which supplies methyl-B12, for example, in 5 mg sublingual doses. Incertain embodiments, the method of the present invention involvesadministering a composition containing 7.5-15 mg L-methylfolate. Instill other embodiments, the method of the present invention involvesadministering a composition containing 5.6 mg L-methylfolate, 2 mgmethylcobalamin, and 600 mg N-acetylcysteine. In certain otherembodiments, the method of the present invention involves administeringa composition containing 3 mg L-methylfolate, 35 mg pyridoxal5′-phosphate (an active form of vitamin B6), and 2 mg methylcobalamin(methyl-B12).

The present invention involves treatment of subject organisms for opticdisorders using one or more downstream folate compounds and/ormethyl-B12, and, optionally, one or more of vitamin B6 and vitamin D3.The present inventor has unexpectedly found that optic disorders, suchas optic neuropathies, can be effectively treated, or the symptomsthereof can be effectively reduced, by administering to those subjectorganisms an effective amount of one or more downstream folate compoundsand methyl-B12, either individually or in combination, and optionally incombination with one or more of vitamin B6 and vitamin D3.

To identify subject organisms with optic disorders, some form ofexamination and/or testing is typically performed. Such testing is wellknown to persons of ordinary skill in the art and can include a completeeye exam, including visual field analysis, retinal photographs, and/orlaser scanning. In addition, a determination as to whether the subjectorganism is non-folic acid-deficient can optionally be made througheither testing/analysis or review of dietary folic acid intake, asdescribed above.

In certain embodiments, testing or other analysis is done to determinewhether the subject organism possesses some form of malfunction in thefolate and/or BH4 cycles. Such testing is well known to persons ofordinary skill in the art and includes genetic testing to determine thepresence or absence of one or both of the C677T and A1298C mutations.

Useful testing to determine whether the subject organism possesses someform of malfunction in the folate and/or BH4 cycles also includes a testto determine if the subject organism possesses elevated levels ofhomocysteine, as excess homocysteine can be indicative of a malfunctionin the folate cycle due to the interaction between the methionine andfolate cycles. Such tests are well known to persons of ordinary skill inthe art and include a homocysteine blood test. Another useful test whichcan be employed is a test to determine whether the subject organismpossesses levels of vitamin B-12 that are within the normal range. Inaddition to determining whether an individual is vitamin B-12 deficient,such a test is useful, for example, to determine the cause of theelevated homocysteine levels, since elevated homocysteine can alsoresult from a vitamin B-12 deficiency, as vitamin B-12 is also involvedin the conversion of homocysteine to methionine. Such tests are wellknown to persons of ordinary skill in the art and include a vitamin B-12blood test. In certain preferred embodiments, a homocysteine blood testwill be performed along with a vitamin B-12 blood test and an analysisof the subject organism's dietary folate intake to determine whether thesubject organism 1) consumes adequate folic acid, and therefore is notfolic acid deficient, 2) has vitamin B-12 levels that are within thenormal range, and therefore is not vitamin B-12 deficient, and 3)possesses excess homocysteine, and therefore, in light of the resultsof 1) and 2), appears to have a malfunction in the folate pathway.Testing can also be done to determine if the subject organism is vitaminD deficient, such as a 25-hydroxy vitamin D blood test.

Treatment of a non-folic acid-deficient subject organism according tothe present invention is accomplished by supplying that subject organismwith an effective amount of one or more downstream folate compounds. Asdescribed above, such compounds can include one or more of DHF, THF,5FITHF, 5,10-METHF, and L-methylfolate. Also as discussed above, thedownstream folate compound(s) can be administered in one or more dosesat regular intervals for a period of days to years.

In addition to administering downstream folate compound(s), in certainembodiments, the method further involves reducing the subject organism'sfolic acid intake. Such a reduction in intake can be accomplished in anysuitable manner. Methods for reducing folic acid intake are well knownto persons of ordinary skill in the art and include reducing the amountof folic acid consumed through dietary supplements and/or reducing theintake of folic acid fortified foods, such as processed foods, includingfortified breads and cereals.

In one particular embodiment, the method involves identifying anon-folic acid-deficient person suffering from an optic neuropathy, anda) administering to that person 1 mcg to 25 mg per day ofL-methylfolate, and b) decreasing the person's intake of folic acid.

In another particular embodiment the method involves 1) identifying anon-folic acid-deficient person with a) reduced visual acuity, b) anoptic disorder selected from the group consisting of neuropathy,retinopathy, macular degeneration, or atrophy, and c) one or both of theC677T and A1298C mutations; and 2) a) administering to that person 1-25mg per day of L-methylfolate, and b) decreasing the person's intake offolic acid. In certain particular embodiments, folic acid intake isdecreased by 1-4 mg per day.

In other embodiments, the method involves administering methyl-B12. Incertain embodiments, the methyl-B12 is administered in an amount of1-2.5 mg per day. In certain embodiments an effective amount ofmethyl-B12 is administered alone to treat an optic disorder. In certainother embodiments, the methyl-B12 is administered in conjunction with adownstream folate compound. In still further embodiments, folate andmethyl-B12 are administered in conjunction with one or more of vitaminB6 and vitamin D3.

In certain preferred embodiments, the method involves 1) identifying asubject organism with an optic disorder; 2) testing the subject organismto determine if it possesses one or both of the C677T and A1298Cpolymorphisms; 3) testing the subject organism to determine if itpossesses above normal homocysteine levels and below normal vitamin B12and vitamin D levels; and) administering to the subject organism aneffective amount of a downstream folate compound and methyl-B12 and,optionally, one or more of vitamin B6 and vitamin D3.

Following treatment, the effectiveness of the treatment can bedetermined by again administering some form of testing or examination todetermine the presence and/or severity of pathological condition(s)and/or symptom(s) wherein a reduction in the presence and severity ofpathological condition(s) and/or symptom(s) indicates that the treatmentmethod was effective. Such a reduction in the presence and/or severityof pathological condition(s) and/or symptoms can be readily determinedby persons of ordinary skill in the art and includes improved visualacuity, improved field defect, reduced headaches, reduced drusen, andreduced papillitis.

EXAMPLES

The present invention is further defined in the following Examples. Itshould be understood that these Examples, while indicating preferredembodiments of the invention, are given by way of illustration only.

Example 1

Patient 1 was a 32-year-old white female who presented with headaches,blurred vision, and a visual acuity of 20/50. A detailed dietary historyindicated that she was not at risk for folic acid deficiency. She wasevaluated medically and diagnosed as having optic nerve head drusen andtoxic optic neuropathy. In addition, through various blood tests, it wasdetermined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 2.8-15 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and D3 supplements, andtold to reduce intake of processed foods as much as possible, such as byswitching to organic foods. After 30 days, she was reexamined and foundto no longer have the above-described symptoms and to have a normalvisual acuity of 20/20.

Example 2

Patient 2 was a 16-year-old white female who presented with headaches,blurred vision, and a visual acuity of 20/30. A detailed dietary historyindicated that she was not at risk for folic acid deficiency. She wasevaluated medically and diagnosed as having toxic optic neuropathy. Inaddition, through various blood tests, it was determined that thispatient had higher than normal levels of homocysteine and below normallevels of vitamin B-12 and 25-hydroxy vitamin D. In addition, throughgenetic testing it was determined that the patient had one or both ofthe C677T and A1298C polymorphisms. The patient was placed on a regimenof 2.8-15 mg L-methylfolate and 1-2.5 mg methyl-B12 per day, in additionto vitamin B6 and D3 supplements, and told to reduce intake of processedfoods as much as possible, such as by switching to organic foods. After60 days, she was reexamined and found to no longer have theabove-described symptoms and to have a normal visual acuity of 20/20.

Example 3

Patient 3 was an 8-year-old white male who presented with headaches,loss of vision, and a visual acuity of 20/40. A detailed dietary historyindicated that he was not at risk for folic acid deficiency. He wasevaluated medically and diagnosed as having papillitis and toxic opticneuropathy. In addition, through various blood tests, it was determinedthat this patient had higher than normal levels of homocysteine andbelow normal levels of vitamin B-12 and 25-hydroxy vitamin D. Inaddition, through genetic testing it was determined that the patient hadone or both of the C677T and A1298C polymorphisms. The patient wasplaced on a regimen of 2.8-15 mg L-methylfolate and 1-2.5 mg methyl-B12per day, in addition to vitamin B6 and D3 supplements, and told toreduce intake of processed foods as much as possible, such as byswitching to organic foods. After 30 days, he was reexamined and foundto no longer have the above-described symptoms and to have a normalvisual acuity of 20/20.

Example 4

Patient 4 was a 19-year-old white male who presented with headaches,loss of vision, visual field loss, and a visual acuity of 20/80. Adetailed dietary history indicated that he was not at risk for folicacid deficiency. He was evaluated medically and diagnosed as havingburied optic nerve head drusen and toxic optic neuropathy. In addition,through various blood tests, it was determined that this patient hadhigher than normal levels of homocysteine and below normal levels ofvitamin B-12 and 25-hydroxy vitamin D. In addition, through genetictesting it was determined that the patient had one or both of the C677Tand A1298C polymorphisms. The patient was placed on a regimen of 2.8-15mg L-methylfolate and 1-2.5 mg methyl-B12 per day, in addition tovitamin B6 and D3 supplements, and told to reduce intake of processedfoods as much as possible, such as by switching to organic foods. After6 months, he was reexamined and found to no longer have theabove-described symptoms and to have a normal visual acuity of 20/20.

Example 6

Patient 5 was a 34-year-old white female who presented with headaches,loss of vision, visual field loss, and a visual acuity of 20/60. Adetailed dietary history indicated that she was not at risk for folicacid deficiency. She was evaluated medically and diagnosed as havingpapillitis. In addition, through various blood tests, it was determinedthat this patient had higher than normal levels of homocysteine andbelow normal levels of vitamin B-12 and 25-hydroxy vitamin D. Inaddition, through genetic testing it was determined that the patient hadone or both of the C677T and A1298C polymorphisms. The patient wasplaced on a regimen of 2.8-15 mg L-methylfolate and 1-2.5 mg methyl-B12per day, in addition to vitamin B6 and D3 supplements, and told toreduce intake of processed foods as much as possible, such as byswitching to organic foods. After 30 days, she was reexamined and foundto no longer have the above-described symptoms and to have a normalvisual acuity of 20/20.

Example 6

Patient 6 was an 11-year-old white female who presented with headaches,visual field defect, and a reduced visual acuity of 20/40. A detaileddietary history indicated that she was not at risk for folic aciddeficiency. She was evaluated medically and diagnosed as havingpapillitis and toxic optic neuropathy. In addition, through variousblood tests, it was determined that this patient had higher than normallevels of homocysteine and below normal levels of vitamin B-12 and25-hydroxy vitamin D. In addition, through genetic testing it wasdetermined that the patient had one or both of the C677T and A1298Cpolymorphisms. The patient was placed on a regimen of 2.8-15 mgL-methylfolate and 1-2.5 mg methyl-B12 per day, in addition to vitaminB6 and D3 supplements, and told to reduce intake of processed foods asmuch as possible, such as by switching to organic foods. After 30 days,she was reexamined and found to no longer have the above-describedsymptoms and to have a normal visual acuity of 20/20.

Example 7

Patient 7 was a 9-year-old white female who presented with headaches,visual field defect, and a reduced visual acuity of 20/40. A detaileddietary history indicated that she was not at risk for folic aciddeficiency. She was evaluated medically and diagnosed as havingpapillitis and buried drusen. In addition, through various blood tests,it was determined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 2.8-15 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and D3 supplements, andtold to reduce intake of processed foods as much as possible, such as byswitching to organic foods. After 6 months, she was reexamined and foundto no longer have the above-described symptoms and to have a normalvisual acuity of 20/20.

Example 8

Patient 8 was a 51-year-old white female who presented with headaches,visual field defect, and a reduced visual acuity of 20/200. A detaileddietary history indicated that she was not at risk for folic aciddeficiency. She was evaluated medically and diagnosed as having ischemicoptic neuropathy. Previously she had been twice diagnosed as having anunknown and untreatable eye disorder that would progress to the point ofblindness. In addition, through various blood tests, it was determinedthat this patient had higher than normal levels of homocysteine andbelow normal levels of vitamin B-12 and 25-hydroxy vitamin D. Inaddition, through genetic testing it was determined that the patient hadone or both of the C677T and A1298C polymorphisms. The patient wasplaced on a regimen of 2.8-15 mg L-methylfolate and 1-2.5 mg methyl-B12per day, in addition to vitamin B6 and D3 supplements, and told toreduce intake of processed foods as much as possible, such as byswitching to organic foods. After one year, she was reexamined and foundto no longer have the above-described symptoms and to have a normalvisual acuity of 20/20.

Example 9

Patient 9 was a 20-year-old white female who presented with migraineheadaches, visual field defect, and a visual acuity of 20/50. A detaileddietary history indicated that she was not at risk for folic aciddeficiency. She had been previously diagnosed as having papillitis. Inaddition, through various blood tests, it was determined that thispatient had higher than normal levels of homocysteine and below normallevels of vitamin B-12 and 25-hydroxy vitamin D. In addition, throughgenetic testing it was determined that the patient had one or both ofthe C677T and A1298C polymorphisms. The patient was placed on a regimenof 2.8-15 mg L-methylfolate and 1-2.5 mg methyl-B12 per day, in additionto vitamin B6 and D3 supplements, and told to reduce intake of processedfoods as much as possible, such as by switching to organic foods. After6 months, she was reexamined and found to no longer have theabove-described symptoms and to have a normal visual acuity of 20/20.

Example 10

Patient 10 was a 31-year-old white female who presented with visualfield defect and a visual acuity of 20/60. A detailed dietary historyindicated that she was not at risk for folk acid deficiency. She wasevaluated medically and diagnosed as having toxic optic neuropathy. Inaddition, through various blood tests, it was determined that thispatient had higher than normal levels of homocysteine and below normallevels of vitamin B-12 and 25-hydroxy vitamin D. In addition, throughgenetic testing it was determined that the patient had one or both ofthe C677T and A1298C polymorphisms. The patient was placed on a regimenof 2.8-15 mg L-methylfolate and 1-2.5 mg methyl-B12 per day, in additionto vitamin B6 and D3 supplements, and told to reduce intake of processedfoods as much as possible, such as by switching to organic foods. After3 months, she was reexamined and found to no longer have theabove-described symptoms and to have a normal visual acuity of 20/20.

Example 11

Patient 11 was a 60-year-old white male who presented with major visualfield defect and a visual acuity of 20/200. Patient 11 had a visuallyacuity that qualified as legally blind for 53 years. A detailed dietaryhistory indicated that he was not at risk for folic acid deficiency. Hehad been diagnosed as having optic atrophy at age 7. In addition,through various blood tests, it was determined that this patient hadhigher than normal levels of homocysteine and below normal levels ofvitamin B-12 and 25-hydroxy vitamin D. In addition, through genetictesting it was determined that the patient had one or both of the C677Tand A1298C polymorphisms. The patient was placed on a regimen of 2.8-15mg L-methylfolate and 1-2.5 mg methyl-B12 per day, in addition tovitamin B6 and D3 supplements, and told to reduce intake of processedfoods as much as possible, such as by switching to organic foods. After3 months, he was reexamined and found to have improved performance onall tests administered and to have a greatly improved visual acuity of20/40.

Example 12

Patient 12 was a 68-year-old male who presented with a visual acuity of20/100. A detailed dietary history indicated that he was not at risk forfolic acid deficiency. He was evaluated medically and diagnosed ashaving hypertension retinopathy resulting in detachment. In addition,through various blood tests, it was determined that this patient hadhigher than normal levels of homocysteine and below normal levels ofvitamin B-12 and 25-hydroxy vitamin D. In addition, through genetictesting it was determined that the patient had one or both of the C677Tand A1298C polymorphisms. The patient was placed on a regimen of 7.5 mgL-methylfolate and 1-2.5 mg methyl-B12 per day, in addition to vitaminB6 and D3 supplements, and told to reduce intake of processed foods asmuch as possible, such as by switching to organic foods. After 6 months,he was reexamined and found to have an improved visual acuity of 20/25.

Example 13

Patient 13 was a 75-year-old female who presented with a visual acuityof 20/70. A detailed dietary history indicated that she was not at riskfor folic acid deficiency. She was evaluated medically and diagnosed ashaving diabetic retinopathy. In addition, through various blood tests,it was determined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 7.5 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and D3 supplements, andtold to reduce intake of processed foods as much as possible, such as byswitching to organic foods. After 30 days, she was reexamined and foundto have a greatly improved visual acuity of 20/30.

Example 14

Patient 14 was a 20-year-old female who presented with a visual acuityof 20/50. A detailed dietary history indicated that she was not at riskfor folic acid deficiency. She was evaluated medically and diagnosed ashaving toxic optic neuropathy. In addition, through various blood tests,it was determined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 2.8 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and D3 supplements, andtold to reduce intake of processed foods as much as possible, such as byswitching to organic foods. After 30 days, she was reexamined and foundto have a normal visual acuity of 20/20.

Example 15

Patient 15 was a 16 year old male who presented with a visual acuity of20/100 and 20/60 in the right and left eyes, respectively. A detaileddietary history indicated that he was not at risk for folic aciddeficiency. He was evaluated medically and diagnosed as having viraloptic neuropathy. In addition, through various blood tests, it wasdetermined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 7.5 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and D3 supplements, andtold to reduce intake of processed foods as much as possible, such as byswitching to organic foods. After one year, he was reexamined and foundto have a greatly improved visual acuity of 20/40 and 20/30 in the rightand left eyes, respectively.

Example 16

Patient 16 was a 60-year-old female who presented with a visual acuityof 20/30 and 20/200 in the right and left eyes, respectively. A detaileddietary history indicated that she was not at risk for folic aciddeficiency. She was evaluated medically and diagnosed as having vitreoushemorrhage, hypertension, and diabetes. In addition, through variousblood tests, it was determined that this patient had higher than normallevels of homocysteine and below normal levels of vitamin B-12 and25-hydroxy vitamin D. In addition, through genetic testing it wasdetermined that the patient had one or both of the C677T and A1298Cpolymorphisms. The patient was placed on a regimen of 15 mgL-methylfolate and 1-2.5 mg methyl-B12 per day, in addition to vitaminB6 and D3 supplements, and told to reduce intake of processed foods asmuch as possible, such as by switching to organic foods. After 60 days,she was reexamined and found to have a normal visual acuity of 20/20 inboth eyes.

Example 17

Patient 17 was a 7-year-old male who presented with a visual acuity of20/30 and 20/25 in the right and left eyes, respectively. A detaileddietary history indicated that he was not at risk for folic aciddeficiency. He was evaluated medically and diagnosed as having toxicoptic neuropathy. In addition, through various blood tests, it wasdetermined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 2.8 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and D3 supplements, andtold to reduce intake of processed foods as much as possible, such as byswitching to organic foods. After 60 days, he was reexamined and foundto have a normal visual acuity of 20/20 in both eyes.

Example 18

Patient 18 was a 17-year-old male who presented with a visual acuity of20/60 and 20/50 in the right and left eyes, respectively. A detaileddietary history indicated that he was not at risk for folic aciddeficiency. He was evaluated medically and diagnosed as having maculardegeneration. In addition, through various blood tests, it wasdetermined that this patient had higher than normal levels ofhomocysteine and below normal levels of vitamin B-12 and 25-hydroxyvitamin D. In addition, through genetic testing it was determined thatthe patient had one or both of the C677T and A1298C polymorphisms. Thepatient was placed on a regimen of 7.5 mg L-methylfolate and 1-2.5 mgmethyl-B12 per day, in addition to vitamin B6 and 10,000 IU vitamin D3supplements, and told to reduce intake of processed foods as much aspossible, such as by switching to organic foods. After 60 days, he wasreexamined and found to have a greatly improved visual acuity of 20/30and 20/25 in the right and left eyes, respectively.

Example 19

A population of approximately 200 individual patients of mixed race andgender ranging in age from 3-80 years old, each with an optic disorder,was collected. Each patient was evaluated using a complete eye examincluding visual field analyses, retinal photographs, laser scanning andultra sound to determine presence, type, and severity of the opticdisorder. The optic disorders present in the study included toxic opticneuropathy, buried optic nerve head drusen, surfaced optic nerve headdrusen, papillitis, ischemic optic neuropathy, age-related maculardegeneration, retinal hemorrhage (hypertensive and diabetic), andvitreous hemorrhage.

Through various blood tests, it was determined that each patient had oneor more of higher than normal levels of homocysteine, below normallevels of vitamin B-12, and below normal levels of 25-hydroxy vitamin D.In addition, through genetic testing it was determined that each patienthad one or both of the C677T and A1298C polymorphisms. Following initialtesting, each patient was placed on a regimen of 1-15 mg L-methylfolateand 1-2.5 mg methyl-B12 per day, as well as supplemental vitamin B6 andD3, all supplied either in a single dose or multiple doses. Each patientwas also told to reduce intake of processed foods as much as possible,such as by switching to organic alternatives. The amount of folateadministered was reduced for individuals who successfully reduced theirfolic acid intake and was increased for individuals who did notsuccessfully reduce folic acid intake. Every 30 days, each patient wasreexamined/reevaluated to determine the effectiveness of the treatment.

In approximately 50% of the patient population, improved visual acuitywas found to exist within 30 days; in approximately 75% of the patientpopulation, improved visual acuity was found to exist within 60 days; inapproximately 95% of the patient population, improved visual acuity wasfound to exist within 6 months; and in approximately 100% of the patientpopulation, improved visual acuity was found to exist within 1 year.

The present invention is not limited to the embodiments described andexemplified above, but is capable of variation and modification.

The invention claimed is:
 1. A method of improving or alleviating avision related headache or migraine in a non-folic acid deficientsubject organism suffering from an optic disorder and vision relatedheadache or migraine, the method comprising administering to the subjectorganism an effective amount of one or more compounds containing folatefound downstream of folic acid in the folate cycle, wherein the subjectorganism comprises one or both of a C677T or a A1298C mutation, andwherein the one or more compounds containing folate found downstream offolic acid in the folate cycle are selected from the group consisting of5-formyltetrahydrofolate, DHF, THF, 5FITHF, 5,10-METHF, andL-methylfolate.
 2. The method of claim 1, wherein the subject organismpossesses both of the C677T and the A1298C mutations.
 3. The method ofclaim 1, wherein the optic disorder is selected from the groupconsisting of optic neuropathy, retinopathy, macular degeneration oroptic atrophy.
 4. The method of claim 1, wherein the subject organism isa human.
 5. The method of claim 1, further comprising decreasing thesubject organism's intake of folic acid.
 6. The method of claim 1,wherein the one or more compounds containing folate found downstream offolic acid in the folate cycle comprise L-methylfolate.
 7. The method ofclaim 6, wherein the L-methylfolate is provided in a dose of 1 mcg to 25mg/day.